Regulation of mRNA translation is one of the most immediate cell response to any form of stress. It is initiated by stress sensing kinases, all of which phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (EIF2A). This results in repression of global protein synthesis but is accompanied by selective translation of proteins vital for cell survival and recovery from stress. To restore cellular homeostasis and to reverse EIF2A signaling, de-phosphorylation of EIF2A is regulated by protein phosphatase 1 (PP1) in complex with one of its regulatory subunits and globular actin (G-actin). G-actin therefore, limits PP1 activity although how cellular actin dynamics are modified to regulate PP1 activity is not known. EIF2A signaling increases translation of activating transcription factor 4 (ATF4) to promote expression of genes involved in stress remediation such as autophagy genes. Conversely, if the stress is unresolved ATF4 regulates the transcription of genes that promote cell death to eliminate damaged cells. The control switch that modulates the cells stress response between survival and death governs the initiation of most inflammatory diseases. In line with that, chronic activation of EIF2A signaling is associated with mucosal inflammation in patients with Crohn?s disease (CD). Despite this, the molecular basis of EIF2A signaling in intestinal epithelial cells (IECs) remains unidentified. We made the novel observation that the IEC actin cytoskeleton fulfils a general function as a biosensor of cell health and regulates EIF2A signaling to establish if the stressed cell will survive or die. We show that by regulating cellular actin dynamics, two homologous actin-severing proteins villin1 and gelsolin integrate stress signaling pathways with cell fate pathways. Using the villin1/gelsolin double knockout mice we show that when the crosstalk between the IEC actin cytoskeleton and EIF2A signaling does not function properly, chronic inflammation ensues. As a result, DKO mice develop spontaneous ileitis that resembles functionally, histologically and clinically human CD. Moreover, our studies with mouse models of CD and CD patient samples indicate that defects in the crosstalk between IEC actin cytoskeleton and EIF2A signaling could be a universal feature of CD. We propose that studying how these pathways normally function in the IECs and how they go awry can provide basic insight into events that drive CD pathogenesis but can also identify novel treatment strategies for CD. We present an innovative mechanistic approach using state-of-the-art techniques that combine the use of IEC lines, transgenic and validated mouse models of disease, and patient samples. The goal of the study is: (1) to characterize the molecular mechanism(s) by which the crosstalk between the actin cytoskeleton and stress signaling determines IEC fate; (2) to determine how defects in the crosstalk between actin cytoskeleton and stress signaling contribute to CD pathogenesis; (3) and to test in vivo and ex vivo in enteroids from mouse models of CD and CD patient samples, the therapeutic benefits of targeting these defects. Our study will advance scientific discovery and could lead to translation of the basic science to model novel therapies to advance CD patient care.